Introduction

Oral mucositis (OM) is an important complication related to anti-neoplastic therapy, such as chemotherapy (CT), radiotherapy (RT), radio-chemotherapy (RT-CT) and hematopoietic stem cell transplantation (HSCT) [1, 2]. Pain and difficulty eating have been associated with a negative impact on the patient’s quality of life [3, 4]. In addition, OM is associated with an increased risk for systemic infections [5, 6] and high financial costs [1, 7].

The Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) has published clinical practice guidelines for the management of OM since 2003, with updates published in 2007, 2014 and 2019–20 [8,9,10,11,12,13,14,15,16]. The guidelines are presented according to the following categories of interventions: (1) anti-inflammatory; (2) antimicrobials, mucosal coating agents, anesthetics, and analgesics; (3) basic oral care; (4) cryotherapy; (5) growth factors and cytokines; (6) photobiomodulation (PBM); and (7) natural and miscellaneous agents. Studies on the interventions for gastrointestinal mucositis were reviewed too [9].

Although high-quality studies investigating OM in pediatric patients are still scarce, there has been some increase in the literature pertaining to this population. Therefore, it is timely to synthesize the available evidence on the management of mucositis in this sub-population.

As part of a better understanding of the MASCC/ISOO clinical practice guidelines for the management of cancer therapy-induced OM, the aim of this sub-analysis is to highlight the evidence related to OM management in the pediatric patient population and to focus on unique considerations.

Methods

The methods related to this sub-analysis are described in detail in Ranna et al. [17]. Briefly, a literature search for relevant papers indexed from January 1, 2011, to June 2016 was conducted using PubMed and Web Science, with papers selected for review based on defined inclusion and exclusion criteria [17]. Additionally, the literature review identified manually randomized controlled trials (RCT) published until July 2019. The list of keywords used by all sections is detailed in Ranna et al. and in the respective section’s articles [8,9,10,11,12,13,14,15,16]. Studies were scored for their level of evidence (LoE) based on Somerfield criteria [18], and flaws were listed according to Hadorn criteria [19]. A well-designed study was defined as a study with no major flaws per the Hadorn criteria. Findings from the reviewed studies were merged with the evidence examined in the previous MASCC/ISOO guideline update, culminating in a systematic review of all literature until March 2020. Then, data was integrated into the guidelines based on the LoE for each intervention. Studies were grouped based on (1) the aim of the intervention (prevention or treatment of mucositis), (2) the cancer treatment modality (RT, CT, RT-CT or HSCT with or without total body irradiation (TBI), (3) the route of administration of the intervention and (4) the agent. Additionally, publications on the pediatric patient population were reviewed from each section and data about patient compliance with the treatment and adverse effects (AEs) were collected using a standard electronic form. Guidelines of this sub-analysis are presented based on the category of intervention.

Results

The literature search identified a total of 10,195 papers from all sections, which were triaged. Following the merge with the papers included in the previous MASCC/ISOO guidelines, 340 (175 RCT) papers were included in the systematic review. For the pediatric sub-analysis, 45 papers were included, 20 RCTs, 6 comparator RCTs (randomizing to either another intervention or to an active control), 4 non-randomized comparative (comparing an intervention to a placebo-control or no treatment), 1 cross-over, 5 before-and-after, 4 case-control, and 5 cohort studies.

Efficacy studies on basic oral care

Multi-agent combination oral care protocols

The preventive efficacy of combined multi-agent oral care protocols for pediatric patients with hematologic malignancies treated with CT regimens were assessed in 5 studies (1 RCT, 3 comparative studies, and 1 before-and-after study) [20,21,22,23,24]. The RCT [20] found no significant difference in OM incidence between the experimental group that received a combination of enhanced oral physiotherapy, use of 0.05% non-alcoholic fluoride mouthwashes daily and 20% miconazole oral gel applications (n = 5) and the control group with no intervention (n = 7). The findings from the 4 remaining non-RCTs [21,22,23,24] consistently indicated that the implementation of a multi-agent combination of oral care protocols is beneficial for the prevention of OM or pain during CT for pediatric cancer patients (Tables 1 and 2).

Table 1 Studies reported for various active agents/intervention, overall level of evidence (all ages), and guideline determination (all ages)
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Table 2 Studies reported for each active agent, patient age and sample size
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Patient education

A single before-and-after study including hematologic and non-hematologic pediatric cancer patients (n = 16) concluded that both the degree of OM and OM-related pain decreased (p < 0.05) when patients were given mouth care education before CT and when they regularly performed mouth care (Tables 1 and 2) [25].

Chlorhexidine

Three studies (2 RCTs and 1 comparative study) assessed OM outcomes in pediatric cancer patients (Tables 1, 2, 3, 4 and 5) [26,27,28]. The RCT, which compared 23 patients in the intervention group with 24 in a placebo group, concluded that 0.12% chlorhexidine mouthwash did not significantly reduce the incidence of OM in pediatric HSCT recipients [28]. The comparative study analyzed 14 pediatric patients (7 patients each for both the experimental and control group) treated with intensive CT regimens for hematologic malignancies and found positive results on the effectiveness of chlorhexidine 0.12% in reducing incidence of OM in the experimental group (p < 0.05) [27]. The comparator RCT compared chlorhexidine to benzydamine and the details are given in the next paragraph under benzydamine (Tables 4 and 5) [26].

Table 3 Studies reported for each active agent, arms, adverse events and tolerability, and patient’s compliance
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Table 4 Comparator studies for various agents, overall level (all ages), and guideline determination (all ages)
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Table 5 Comparator studies for various agents, arms, adverse events and tolerability, and patient’s compliance
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Efficacy studies about anti-inflammatory agents

Benzydamine

There were no RCTs comparing benzydamine to a placebo. A single RCT comparing benzydamine to chlorhexidine reported their findings in 3 publications (Tables 4 and 5) [26, 29, 30]. The aim of this RCT was the prevention of OM in pediatric patients undergoing CT for hematologic and solid cancer. The study was designed as a non-blinded cross-over trial, where each patient behaved as their own control. The results of this RCT reported benzydamine was not superior to chlorhexidine. Another small cross-over study of 4 patients assessing benzydamine for the treatment of OM in pediatric patients with hematologic malignancies and solid tumors treated with CT reported benzydamine was not effective in reducing pain (Tables 1, 2 and 3) [31]. In this study, benzydamine mouthwash was being alternated with Hospital for Sick Children (HSC) mouthwash (nystatin 7000 U/mL, lidocaine viscous 0.58 mL/mL in NaCl 0.9%) over 2 cycles.

Efficacy studies about antimicrobials, mucosal coating agents, anesthetics, and analgesics

Sucralfate

A single double-blind RCT assessed the effectiveness of swish and swallow suspension with sucralfate in hematological cancer pediatric patients experimental (n = 24) and control (n = 24) groups who underwent CT (Tables 1, 2 and 3) [32]. Patients receiving sucralfate reported less oral discomfort (p = 0.06) but there was no statistically significant difference in pain severity between the groups.

Polymyxin-tobramycin-amphotericin B lozenges

A single comparator study evaluated the use of topical polymyxin-tobramycin-amphotericin B lozenges (n = 12) to a mouthwash containing diphenhydramine, and topical anesthetic in an oral suspension of aluminum hydroxide and magnesium hydroxide (n = 14) in the treatment of OM in hematological and solid cancer pediatric patients that underwent HSCT with or without TBI (Tables 4 and 5) [33]. The OM score in the group taking polymyxin-tobramycin-amphotericin-B was significantly lower (p < 0.05). The 2014 mucositis guidelines paper of the MASCC/ISOO reported that the clinical difference was small [34].

Morphine

A double-blind cross-over RCT evaluating the use of morphine in pediatric patients that underwent autologous or allogenic HSCT found no statistical difference in daily pain scores between the compared groups (Tables 4 and 5) [35]. There were two groups that differed in the orders of the interventions. The first group was composed of pediatric patients that received morphine followed by hydromorphone and then morphine (n = 5). The second group initiated the protocol with hydromorphone followed by morphine and then hydromorphone (n = 5), both delivered as patient-controlled analgesia (PCA) protocol. A second RCT evaluated pediatric patients that underwent HSCT with or without TBI and compared OM-related pain outcomes between a PCA protocol and a continuous infusion regimen (Tables 4 and 5) [36]. It concluded that there was a significantly lower morphine intake in the PCA group (p < 0.01), but there was no difference in pain intensity between the two groups.

Ketamine

A single before-and-after study [37] analyzed the addition of ketamine to morphine PCA or nurse-controlled analgesia (NCA) protocols in regard to OM-related pain relief. This study showed that ketamine added either to a PCA or NCA protocol improved analgesic efficacy in pediatric patients with hematologic and solid malignancies that underwent variable CT regimens (p = 0.01) (Tables 1, 2 and 3).

Efficacy studies about growth factors and cytokines

Keratinocyte growth factors

A single RCT, published in 2 parts, about intravenous (IV) keratinocyte growth factors (KGF-1) to prevent OM in pediatric patients undergoing HSCT reported the results of 27 patients treated with either IV KGF-1 or placebo (Tables 1, 2 and 3) [38, 39]. This RCT showed effectiveness in reducing the severity (p = 0.03) and duration of OM (p < 0.001). Three other studies (1 cohort [40] and 3 case-control studies [41,42,43]) reported that KGF-1 was effective in reducing mucositis severity or duration, and that patients complied well.

Granulocyte colony-stimulating factor

A single RCT studied the effect of subcutaneous (SC) granulocyte colony-stimulating factor (G-CSF) included 148 pediatric patients with hematologic malignancies treated with high-dose CT. The results indicated that the use of G-CSF was ineffective to prevent severe OM (Tables 1, 2 and 3) [44].

Granulocyte-macrophage colony-stimulating factor

There is limited evidence for the use of IV granulocyte-macrophage colony-stimulating factor (GM-CSF) in pediatric patients undergoing HSCT for the prevention of OM (Tables 1, 2 and 3) [45]. This cohort reported of non-significant reduction in duration of OM.

Transforming growth factor-β—nutrition or mouthwash

A single RCT on the use of transforming growth factor-β (TGF-β) for the prevention of OM in 25 pediatric patients treated with CT (Tables 1, 2 and 3) [46] concluded that TGF-β is not effective for the prevention of CT induced OM.

Efficacy studies about natural and miscellaneous agents

Supersaturated calcium phosphate rinse

A single RCT of 29 pediatric patients undergoing HSCT or CT reported the efficacy of supersaturated calcium phosphate rinse (SCPR) (Caphosol®, EUSA Pharma, Hemel Hempstead, UK) for the treatment of OM. The study reported that SCPR is ineffective for the treatment of OM in alleviating severity, duration, and pain severity (Tables 1, 2 and 3) [47].

Glutamine

A single RCT including 118 patients [48] and a case-control study [49] that assessed the efficacy of parenteral glutamine in pediatric patients reported no beneficial effect of glutamine (parenteral) for prevention of OM in HSCT (Tables 1, 2 and 3). Contrary to this a single RCT on oral glutamine based on the [50] same patient population (n = 120) showed glutamine to be effective in reducing pain duration (p = 0.01) and to have a tendency to reduce OM severity. Further, some studies with lower quality designs reported that parenteral glutamine was ineffective in the prevention of OM in patients with hematologic cancer treated with CT [51, 52].

Vitamin E

A single RCT compared topical vitamin E to a placebo for the prevention of OM in hematologic malignancies and solid cancer patients treated with CT failed to demonstrate a reduction in OM severity (Tables 1, 2 and 3) [53]. The sample size was 16 patients; however, it is unclear how many patients were in each arm since data was reported per treatment cycle.

Another RCT that evaluated the efficacy of swish and swallow vitamin E compared with pycnogenol or glycerin (vehicle-control) in 72 pediatric patients treated with CT (Tables 1, 2 and 3) [54] reported no significant difference between both active arms. However, the two active arms were effective compared with the control arm for the treatment of OM (p < 0.001).

Calcitriol

A single RCT described the use of calcitriol for the prevention of OM in 28 patients undergoing HSCT due to Fanconi anemia (Tables 1, 2, and 3) [55]. The study did not report considerable benefits for calcitriol in preventing OM.

Honey

A single placebo-controlled RCT of topical honey for the treatment of OM in 90 pediatric patients with hematologic malignancies undergoing CT (Tables 1, 2 and 3) [56] reported the effectiveness of the Trifolium alexandrinum-based honey in reducing the healing time of ulcerative OM. (p = 0.0005). Additionally, a mixture of honey, olive oil-propolis extract, and beeswax (HOPE) was significantly more effective than in the control (p = 0.0056).

Propolis

A single RCT reported the ineffectiveness of topical propolis for the treatment of OM in pediatric patients (n = 40) treated with CT for hematological and solid cancers (Tables 1 and 2) [57].

Traumeel

Two RCTs investigated the use of Traumeel for the prevention of OM in pediatric patients undergoing HSCT (Tables 1, 2 and 3) [58, 59]. The pediatric patients were instructed to swish and swallow in both studies. In the first RCT with hematologic patients (n = 30), Traumeel illustrated a significant reduction in the severity and duration of OM (p < 0.01) [58]. On the other hand, in the second RCT, Traumeel was ineffective for the prevention of OM in pediatric patients with hematologic and solid cancers (n = 181) [59].

Chewing gum

Two RCTs described the use of chewing gum for the prevention of OM in pediatric patients treated with CT for hematologic malignancies and solid cancers (Tables 1, 2 and 3) [60, 61]. In one RCT with 145 pediatric patients, oral care alone was compared with oral care combined with a chewing gum routine [61]. In the other RCT with 130 pediatric patients, the use of chewing gum and “magic mouthwash” (nystatin, diphenhydramine, and aluminum) was compared with “magic mouthwash” alone [60]. Both studies reported chewing gum was not effective to prevent OM.

Pycnogenol

A single RCT reported on pycnogenol compared with vitamin E or a control group and results are presented under the “Vitamin E” section above [54].

Efficacy studies on cryotherapy

One study evaluated the effectiveness of cryotherapy together with the vasoconstrictor propantheline (n = 12), compared to a single intervention (cryotherapy or propantheline; n = 5) and to a control group receiving no treatment (n = 7) for the prevention of OM in pediatric patients undergoing HSCT with or without TBI (Tables 1, 2 and 3) [62]. Cryotherapy was applied 5–10 min before and at least 30 min following the CT infusion. Propantheline was administered at 1.5 mg/kg once daily from the day before CT infusion until one day before the HSCT. The results showed that the combination protocol was significantly more effective in reducing the incidence of severe OM (grades 3–4) compared to the other two groups (p = 0.0069).

Efficacy studies on PBM

The management of OM with intra-oral PBM in a mixed pediatric patient population, including hematologic malignancies and solid cancers, treated with either high-dose CT or HSCT has been described by two studies (Tables 1, 2, 3 and 6) [63, 64]. The RCT with 123 pediatric patients observed the effectiveness of intra-oral PBM in pain reduction (p < 0.005) [63]. A cohort study (n = 18) with intra-oral PBM therapy reported a significant decrease in the severity of OM (p < 0.05) and pain reduction (p < 0.001) [64]

Table 6 Studies addressing photobiomodulation for the management of oral mucositis in pediatric patients
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.

Another cohort study on the effectiveness of extra-oral PBM for the prevention of OM in a mixed pediatric patient population (n = 32), including hematologic malignancies and solid cancers treated with HSCT was reported (Tables 1, 2 and 3) [65]. The results demonstrated a significant reduction in OM-associated pain.

AEs and tolerability

The active agents used in this sub-analysis were generally well tolerated by pediatric patients (Table 3). Interventions for which AEs were reported are detailed below.

Chlorhexidine and benzydamine

Chlorhexidine (0.12–0.2%) and benzydamine (0.15%) have been related to stinging or burning sensations [26, 27, 29, 30]. In an RCT, the dilution of the chlorhexidine and benzydamine mouthwashes with saline or water was required in 6% and 3% of patients, respectively [30]. In another RCT, once OM developed, there was an increase in patients who required dilution of chlorhexidine and benzydamine due to stinging and burning sensations in the oral cavity to 33% and 20% of patients, respectively [29]. Nevertheless, no patient discontinued the use of mouthwashes with both active agents. On the other hand, a small study reported severe oral stinging when benzydamine (0.15%) mouthwash was administered, and 3 out of 4 patients dropped out of the study due to this adverse effect [31].

In addition, a minor taste alteration has been reported by pediatric patients when using chlorhexidine (0.2%) and benzydamine (0.15%); in 6% and 3–9% of patients, respectively [29, 30].

Propolis

A transient burning sensation has been reported by 26.7% of pediatric patients immediately after application of a HOPE mixture [56].

Photobiomodulation

A burning sensation was reported following PBM therapy in 50% of pediatric patients (9 out 18) [64]. Other studies did not report any AEs.

KGF-1

AEs related to KGF-1 were skin rash (22–44% of patients) [38,39,40,41,42], altered taste (10–20%) [38, 39, 42], gingival hyperplasia (11%) [40], a sensation of increased tongue thickness (12.5–16%) [38, 39], lip swelling (11%) [40], pharyngeal plaque (11%) [40], and face edema (11%) [40].

Sucralfate

Eight (33.3%) patients that received a placebo suspension and 4 (16.6%) patients that received a swish and swallow sucralfate suspension experienced cutaneous rash [32].

Morphine and hydromorphone

Patients that underwent a cross-over of morphine and hydromorphone reported mild sedation, nausea, vomiting, and pruritus during the administration of the protocol. Also, 1 patient presented with urinary retention during hydromorphone use, which required urinary catheterization [35]. The single administration of morphine by a PCA or continuous-infusion was associated with mild nausea, concentration issues, and sleepiness during both administered protocols [36].

Ketamine

There was an overall incidence of nausea/vomiting and pruritus related to ketamine in 58% and 34% of patients, respectively. One patient had the ketamine withdrawn after becoming acutely confused during a septic episode and required intensive care [37].

Vitamin E

Vitamin E was associated with an uncomfortable “oily texture” by 12 out of 16 patients in a single RCT [53].

Compliance with treatment

The compliance was reported in 31 out of 45 of the papers (Tables 3 and 5). The compliance of pediatric patients was based on patient self-reports or parental reports. Studies reported compliance as a dichotomic categorical variable (good/poor) [21, 31, 38,39,40,41,42,43, 46, 47, 51,52,53,54,55,56,57,58,59, 62, 64, 65] or as a quantitative analysis [22, 23, 26, 28,29,30, 50, 59, 61].

Compliance was adequate in most of the studied patients, except for some cases. For example, there was a limitation specific to younger children to stay awake during oral cryotherapy application when it was performed in the evening [62].

Discussion

This sub-analysis paper of the MASCC/ISOO clinical practice guidelines for the management of mucositis presented the available evidence regarding interventions for OM in pediatric cancer patients. Although over a dozen studies were large RCTs, the type and quality of the study design, as well as the volume of the studies are not as robust as the evidence in the adult patient population, except for chewing gum. Furthermore, the diversity of the pediatric cancer patients population in these studies, and the combination of experimental agents in a single study protocol, compromise the conclusion about an effective intervention for oral mucositis. Therefore, interventional protocols in pediatric patients need to rely on extrapolation from the currently available evidence for adult cancer patients.

The literature included in this sub-analysis reported of either oral or systemic drug-related AEs. Benzydamine or chlorhexidine necessitates dilution or dose reduction [29, 30]. Drug withdrawal was infrequently needed for benzydamine or ketamine [31, 37]. Notwithstanding, parenteral glutamine was reported to be associated with increased relapse and mortality in adult HSCT patients [66].

In the pediatric oncology setting, specific instruments may be helpful to assess OM and OM-related pain. Depending on the age of the patient, language development, emotional difficulty in expressing themselves, comprehensive skills, and attention capacity, it can be difficult to apply the conventional scales used for adult cancer patient assessment [67]. Some examples such as the Children’s International Mucositis Evaluation Scale [25, 54], a self-reporting scale designed for children with cancer, as well as visual “smiley face” scales, are validated and reliable tools for this population [22, 23, 31, 37, 54, 63, 65]. Among the selected studies in the current sub-analysis, several types of assessment tools were used, and only some of them were adapted for children.

The effectiveness of an experimental intervention relies on its capacity to prevent or mitigate the signs and symptoms of OM, as well as on its acceptance. The acceptance is driven by ease of use and lack of AEs, psycho-emotional state, and general health condition of the patient [29, 62]. In order to overcome the challenges related to pediatric patient acceptance, unique treatment strategies should be employed. For example, the use of popsicles instead of ice or ice water for younger patients undergoing oral cryotherapy may increase compliance during the application [62]. Likewise, extra-oral PBM may be tolerated better than the intra-oral approach [65, 68, 69]. Studies in cancer and non-cancer pediatric patients suggested strategies utilizing cognitive-behavioral approaches may help to handle stressful situations and consequently enhance engagement in children. For example, the use of storyboards, gaming, virtual-reality experiences, medical clowning, animal-assisted therapy, or a parent-guided therapy approach [70,71,72,73,74,75].

Following the timeframe of the literature search of the MASCC/ISOO guidelines update, 15 RCTs were published addressing interventions for the management of OM in pediatric cancer patients. The new RCTs investigated the use of natural & miscellaneous agents [76,77,78,79,80,81,82], PBM therapy [68, 83,84,85,86], oral cryotherapy [87], G-CSF [88], and KGF-1 vs. chlorhexidine mouthwashes [89]. These newer RCTs suggest efficacy for honey and inefficacy for SCPR. The PBM studies had conflicting results and, due to the diverse PBM protocols, it is impossible to conclude about a preferred PBM setting. The long-term effects of these interventions are unknown. Although the speculative benefit of honey on OM prevention, some concerns about an increased risk of dental caries still remains [14].

In summary, this is the first focused view of MASCC/ISOO on guidelines for the management of OM for pediatric patients. It is a detailed sub-analysis of the guidelines that were developed by this group [90]. There is evidence that chewing gum does not prevent OM. In addition, there is intriguing evidence regarding the efficacy of PBM and honey. Despite the absence of high evidence studies, the implementation of basic oral care protocol is very appropriate.